Homeostatic Role and Therapeutic Potential of the Neuroprotective Retinal Lipoxin Circuit

项目概要/摘要 青光眼是视网膜和视神经的慢性变性，是导致不可逆性青光眼的主要原因。 失明，估计影响全球8000万人。它也是最常见的神经退行性疾病 疾病在世界上，影响到约300万美国人，估计29亿美元的年度负担给美国 医疗保健系统。我们对病因学和驱动发病机制的分子机制的理解 青光眼的症状仍然不完全。主要治疗选择仅限于降低眼内压（IOP）。 没有神经保护疗法来预防或挽救定义青光眼的退行性级联反应。 星形胶质细胞是视神经乳头（ONH）结构和副炎症变化的中心驱动因素， 随后，不可逆的视网膜神经节细胞（RGC）死亡。新的证据表明星形胶质细胞 青光眼中的神经保护和促存活活性。这些保护性信号的性质和相关性 仍不清楚我们最近发现了静息视网膜星形胶质细胞分泌的神经保护活性， 被证明是一个以前未知的居民视网膜脂氧素脂质介质电路。脂氧素是一种强效的 专门的促分解脂质介质（SPM），由于其 在抑制和解决其他组织中的局部炎症中的既定作用。我们发现， 脂氧素LXA 4和LXB 4由静息星形胶质细胞和健康视网膜和OHN产生， 脂氧素受体选择性地表达于RGCs，这证实了一种以前未知的直接神经活性 脂氧素这种内在途径响应于视网膜/ONH应激而失调。更重要的是我们 已经证实脂氧素治疗通过增加RGC存活和拯救RGC而具有神经保护作用， RGC在急性神经毒性视网膜损伤模型和慢性IOP依赖性视网膜损伤模型中的功能 青光眼样神经变性。我们假设脂氧素通路是一个重要的旁分泌信号通路 维持神经元稳态和保护视网膜免受压力的机制。在多PI研究中 项目，我们将描述这种新的神经保护网络，定义其作用机制，并探讨其作用机制。 用以下三种方法放大脂氧素回路作为神经保护的治疗靶点的功效 具体目的：1）表征LXA 4和LXB 4在视网膜、ON和星形胶质细胞中形成的机制， 2）定义LXA 4和LXB 4亲的不同作用机制， RGC中的存活信号传导，以及3）研究放大脂氧素回路以防止 和/或阻止RGC退化。这个项目的目标是产生对小说的变革性见解 神经元支持机制及其在损伤或应激后的失调。最重要的是，我们将测试 这种保护回路的放大可以防止或阻止视网膜/视神经变性和视力丧失。

Project Summary/Abstract Glaucoma is a chronic degeneration of the retina and optic nerve, and a leading cause of irreversible blindness, estimated to afflict 80 million people worldwide. It is also the most common neurodegenerative disease in the world, affecting ~3 million Americans with an estimated $2.9 billion annual burden to the US Health Care system. Our understanding of the etiology and molecular mechanisms that drive the pathogenesis of glaucoma remain incomplete. Primary treatment options are limited to lowering intraocular pressure (IOP). There are no neuroprotective therapies to prevent or rescue the degenerative cascades that define glaucoma. Astrocytes are a central driver of structural and parainflammatory changes at the optic nerve head (ONH) and subsequent, irreversible retinal ganglion cells (RGC) death. Emerging evidence indicates that astrocytes have neuroprotective and pro-survival activities in glaucoma. The nature and relevance of these protective signals remains unclear. We recently identified a secreted neuroprotective activity in resting retinal astrocytes, which proved to be a previously unknown resident retinal lipoxin lipid mediator circuit. Lipoxins are a family of potent specialized proresolving lipid mediators (SPMs), which are being developed as drug targets due to their established role in dampening and resolving local inflammation in other tissues. We discovered that two lipoxins, LXA4 and LXB4, are generated by resting astrocytes and in the healthy retina and OHN and that a lipoxin receptor is selectively expressed in RGCs, which identified a previously unknown direct neural activity of lipoxins. This intrinsic pathway is dysregulated in response to retinal/ONH stress. More importantly, we established that therapeutic treatment with lipoxins is neuroprotective by increasing RGC survival and rescuing RGC function in both an acute neurotoxic retinal injury model, and a chronic IOP dependent model of glaucoma like neurodegeneration. We hypothesize that the lipoxin circuit is an important paracrine signaling mechanism to maintain neuronal homeostasis and protect the retina against stress. In a multiple-PI Research Project, we will characterize this novel neuroprotective network, define its mechanism of action and explore the efficacy of amplifying the lipoxin circuit as a therapeutic target for neuroprotection with the following three specific aims: 1) Characterize the mechanism of LXA4 and LXB4 formation in retina, ON, and astrocytes in the context of health and glaucomatous injury, 2) Define the distinct mechanisms of action for LXA4 and LXB4 pro- survival signaling in RGCs, and 3) Investigate the therapeutic potential of amplifying lipoxin circuits to prevent and/or stop RGC degeneration. This goal of this project is to generate transformative insights into a novel neuronal support mechanism and its dysregulation following injury or stress. Most importantly, we will test if amplification of this protective circuit can prevent or stop retinal/optic nerve degeneration and vision loss.